Despite intensive investigation, the etiology of insulin dependent diabetes mellitus (IDDM) remains unclear. Studies in the human, mouse, and rat indicate that a gene or genes in the major histocompatibility complex (MHC) explain some--but not all of the inherited predisposition to the disease. The other genetic factors remain obscure. We propose to use the Diabetes Prone (DP) BB rat, which among the best models of human IDDM with onset and pathogenesis closely resembling the human disease. Using several crosses involving the DP rat, we have been able to map two genes (Iddm1, Iddm2) responsible for IDDM, and have evidence that there is one additional gene (Iddm3) that appears to confer resistance in the Fischer rat. Specifically, we propose to: 1) Map the gene responsible for conferring diabetes resistance in the Fisher Rat. By genotyping backcross progeny with markers from our genetic linkage map of the rat, we will be able to scan the entire genome, simultaneously and identify regions of the genome important in the development of diabetes. 2) Use positional clone techniques to identify Iddm1 and Iddm3. This strategy will require the construction of contigs spanning the gene containing regions. A yeast artificial chromosome (YAC) library will be constructed for the rat and used to make these contigs. Once the genes have been cloned, we will characterize the function of these genes. 3.) Study the role of the MHC in the development of diabetes. The MHC (Iddm2) is well known to play a major role in IDDM, yet the mechanism remains obscure. To study the role of the MHC, we will introgress the MHC from the Fischer and Lewis rats on to a DP background. Genetic markers flanking the MHC will be used to track the introgression. These congenic lines will be used to determine the role of different MHC classes in an otherwise diabetes permissive background. 4) Analysis of Iddm1 and Iddm3 Homologues in Human Pedigrees. Human homologues of Iddm1, Iddm3 and any other non-MHC found to co-segregate with IDDM in the DP rat, will be developed into genetic markers. In collaboration with Ake Lernmark's lab, we will assay these markers in human pedigrees using affected sib-pair analysis and population association studies. These studies should identify genetic loci responsible for diabetes in both the BB rat and man.